Topical compositions and methods for treating psoriasis

ABSTRACT

Topical pharmaceutical compositions comprise a combination of a corticosteroid a retinoid; and methods for treating psoriasis with same.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 62/181,481, filed on Jun. 18, 2015, thecontent of which is relied upon and incorporated herein by reference inits entirety.

BACKGROUND OF THE INVENTION

The present invention relates to topical compositions and methods fortreating psoriasis. In particular, this invention relates to topicalpharmaceutical compositions comprising a combination of activeingredients, and methods using the same, for treating psoriasis. Moreparticularly, this invention relates to topical pharmaceuticalcompositions comprising a combination of a corticosteroid and aretinoid, and methods using the same, for treating psoriasis.

Psoriasis is a chronic skin disease affecting approximately about 2-4percent of the population world-wide. Over seven million people in theUnited States are affected. While the pathogenesis of psoriasis has notyet been fully elucidated, significant evidence indicates that epidermalchanges occur as a secondary response to cellular immune infiltrates inthe skin. Psoriasis is characterized by discrete areas of skininflammation with redness, thickening, intense scaling, and in somecases, itching. The disease has significant impact on the quality oflife of affected individuals, both physically and psychologically. Todaythere is no cure for psoriasis, and treatment is directed at reducingthe severity and extent of the psoriatic plaques and the relatedsymptoms. The primary measurement of treatment success used by the U.S.Food and Drug Administration in evaluating products for the treatment ofpsoriasis is significant overall improvement in psoriasis severity basedon Investigators Global Assessment.

Systemic therapy such as methotrexate, or biologics such as etanercept,adalimumab, infliximab, etc. are the preferred treatment when the skininvolvement is extensive; e.g., ten percent of the body surface area ormore. A large number of those suffering from psoriasis have lessextensive disease, and topical medications are considered a safer andmore prudent alternative in most of these cases. Among the topicaltherapies are anti-inflammatory corticosteroids; particularly, the superpotent ones such as halobetasol propionate, vitamin D derivatives, suchas calcipotriene, a retinoid known as tazarotene, and coal tar. Each ofthe topical therapies has some degree of effectiveness, but each haslimitations in the degree of improvement of the psoriatic plaques thatcan be achieved or the occurrence of adverse effects.

Halobetasol propionate (a topical corticosteroid) is commerciallyavailable and has been used to treat psoriasis for about 20 years ormore at strength of 0.05% in a variety of dosage forms such as creamsand ointments. Halobetasol is quite effective in improving the signs andsymptoms of psoriasis; however both local and systemic adverse effectslimit its chronic use. Treatment duration is limited to 2 weeks by FDA,and signs and symptoms of psoriasis often rebound (worsen) following theend of treatment.

For many years tazarotene (a retinoid) has been commercially availableand has been used to treat psoriasis topically as creams and gels of0.05% and 0.1%. Tazarotene generally shows moderate effectiveness inpsoriasis; however its use in psoriasis is severely limited by localskin irritation. Dermatologists treated psoriasis and achieved goodclinical results using sequential therapy with a corticosteroid in themorning and tazarotene applied in the evening.

The need still exists for more effective and safer topical medicamentswith reduced adverse effects for the management of psoriasis.

SUMMARY OF THE INVENTION

In general, the present invention provides topical compositions andmethods for treating psoriasis.

In one aspect, the present invention provides topical pharmaceuticalcompositions comprising a combination of active ingredients selectedfrom the group consisting of dermatological immune response-modulatingagents and anti-proliferative agents, and methods using the same, fortreating psoriasis.

In another aspect, the present invention provides topical pharmaceuticalcompositions comprising a combination of: (a) a corticosteroid or apharmaceutically acceptable salt or ester thereof; and (b) a retinoid ora pharmaceutically acceptable salt or ester thereof, and methods usingthe same, for treating psoriasis. In one embodiment, such psoriasis isplaque psoriasis.

In still another aspect, the present invention relates to topicalpharmaceutical compositions comprising a combination of: (a) halobetasolor a pharmaceutically acceptable salt or ester thereof; and (b)tazarotene or a pharmaceutically acceptable tazarotenic acid salt, andmethods using the same, for treating psoriasis. In one embodiment, suchpsoriasis is plaque psoriasis.

In yet another aspect, the present invention provides topicalpharmaceutical compositions comprising a combination of: (a) halobetasolor a pharmaceutically acceptable salt or ester thereof; and (b) atazarotene or a pharmaceutically acceptable tazarotenic acid salt or apharmaceutically acceptable non-ethyl ester of tazarotenic acid, andmethods using the same, for treating psoriasis; wherein each of: (a)halobetasol or a pharmaceutically acceptable salt or ester thereof; and(b) tazarotene or a pharmaceutically acceptable tazarotenic acid salt ora pharmaceutically acceptable non-ethyl ester of tazarotenic acid ispresent in the composition at a positive concentration of less than0.09% based on the weight of the composition. A non-ethyl ester oftazarotenic acid is an ester of tazarotenic acid that is not the ethylester. For example, a non-ethyl ester can be methyl, propyl, isopropyl,butyl, isobutyl, pentyl, isopentyl, aryl, phenyl, or naphthyl ester. Inone embodiment, the concentration of halobetasol or a pharmaceuticallyacceptable salt is in the range from about 0.001 to about 0.049 weightpercent (“wt %”); and the concentration of tazarotene or apharmaceutically acceptable tazarotenic acid salt is in the range fromabout 0.001 to about 0.049 wt %.

Other features and advantages of the present invention will becomeapparent from the accompanying drawings and the following detaileddescription and claims.

DETAILED DESCRIPTION OF THE INVENTION

In general, the present invention provides topical compositions andmethods for treating psoriasis.

Throughout this disclosure, unless otherwise indicated, theconcentration of an ingredient of the composition is in percent byweight of the total composition.

In one aspect, the present invention provides topical pharmaceuticalcompositions comprising a combination of active ingredients selectedfrom the group consisting of dermatological immune response-modulatingagents and anti-proliferative agents, and methods using the same, fortreating psoriasis.

In another aspect, a topical pharmaceutical composition of the presentinvention is used to treat or ameliorate psoriasis in patients sufferingfrom moderate to severe plaque psoriasis.

In yet another aspect, a topical pharmaceutical composition of thepresent invention is used to treat or ameliorate psoriasis in patientswith psoriasis covering up to about 12 percent of the body surface area.

The inventors have unexpectedly discovered that a topical dermatologicalcomposition comprising two different active ingredients selected fromthe group consisting of dermatological immune response-modulating agentsand anti-proliferative agents is synergistically more efficacious thanthe combined efficacies of compositions, each comprising only one of theactive ingredients in the treatment of psoriasis. In one aspect, oneactive ingredient is a corticosteroid, and the other active ingredientis a retinoid. Corticosteroids are also known alternatively as steroids,corticoids or glucocorticosteroids.

In particular, the inventors surprisingly discovered that a compositioncomprising halobetasol (a corticosteroid) and tazarotene (a retinoid) issynergistically more efficacious than the combined efficacies (i.e., thesum of the efficacies) of compositions, each comprising only one ofthese active ingredients.

In another aspect, the present invention provides topical pharmaceuticalcompositions comprising a combination of: (a) a corticosteroid or apharmaceutically acceptable salt or ester thereof; and (b) a retinoid ora pharmaceutically acceptable salt or ester thereof, and methods usingthe same, for treating psoriasis.

In one aspect, a corticosteroid included in a composition of the presentinvention is selected from the corticosteroids of class 1. Theclassification of corticosteroids and examples thereof are disclosed inTable 1.

TABLE 1 Class 1 - Superpotent Topical Corticosteroids Clobetasolpropionate Betamethasone dipropionate Halobetasol propionateFluocinonide Diflorasone diacetate

Clobetasol propionate and halobetasol propionate have been used fortreating steroid responsive dermatoses, including psoriasis, always at aconcentration of 0.05%, in various dosage forms including ointments,creams, solutions, sprays, and gels.

Betamethasone dipropionate has been used for treating steroid responsivedermatoses, including psoriasis, always at a concentration of 0.064%equivalent to 0.05% betamethasone, in several dosage forms includingointments, creams, gels and lotions.

Fluocinonide has been used for treating steroid responsive dermatoses,including psoriasis, at various concentrations ranging from 0.001% to0.1%, in various dosage forms including ointments, creams, gels andsolutions. Only the 0.1% formulations have been classified assuperpotent.

Diflorasone diacetate has been used for treating steroid responsivedermatoses, including psoriasis, at various concentration of 0.05%, asan ointment and as a cream. Only ointment formulation has beenclassified as superpotent.

HPA axis suppression from long term use topical preparations containingclobetasol propionate and halobetasol propionate and other super potentcorticosteroids has limited the duration of therapy allowed by FDA. Theduration on therapy allowed in the labeling for super potent topicalcorticosteroids is normally limited to two weeks.

In one aspect, the corticosteroid is present at a concentration belowthat which is presently utilized in topical formulations. Theformulation contains the corticosteroid at a positive concentration lessthan 0.05% w/w.

In certain embodiments of the present invention, a corticosteroid or apharmaceutically acceptable salt or ester thereof is present in thecomposition at a positive concentration of less than 0.05% based on theweight of the composition. Alternatively, the corticosteroid is presentin the composition at a concentration in the range from about 0.001 toabout 0.049 wt %, or from about 0.005 to about 0.04 wt %, or from about0.005 to about 0.035 wt %, or from about 0.005 to about 0.03 wt %, orfrom about 0.005 to about 0.025 wt %, or from about 0.005 to about 0.015wt %, or from about 0.005 to about 0.01 wt %.

In still another aspect, a retinoid included in a composition of thepresent invention is selected from the group consisting of tazarotene,bexarotene, and adapalene. These retinoids are commonly known asthird-generation retinoids.

In yet another aspect, a retinoid belonging to the group known assecond-generation retinoids (such as etretinate and acitretin) may beused in a composition of the present invention for patients who sufferfrom the psoriatic condition.

In one aspect, the retinoid is present at a concentration below thatwhich is presently utilized in topical formulations. For example,tazarotene or tazarotenic acid salt is included in a composition of thepresent invention at a positive concentration less than 0.05 wt %.

In certain embodiments of the present invention, a retinoid or apharmaceutically acceptable salt or ester thereof is present in thecomposition at a positive concentration of less than 0.09% based on theweight of the composition. For example, the retinoid is present in thecomposition at a concentration in the range from about 0.001 to about0.09 wt %, or from about 0.001 to about 0.08 wt %, or from about 0.001to about 0.07 wt %, or from about 0.001 to about 0.06 wt %, or fromabout 0.01 to about 0.09 wt %, or from about 0.01 to about 0.08 wt %, orfrom about 0.01 to about 0.07 wt %, or from about 0.01 to about 0.06 wt%, or from about 0.001 to about 0.049 wt %, or from about 0.005 to about0.045 wt %, or from about 0.005 to about 0.04 wt %, or from about 0.005to about 0.03 wt %, or from about 0.005 to about 0.02 wt %, or fromabout 0.005 to about 0.01 wt %, or from about 0.01 to about 0.049 wt %,or from about 0.01 to about 0.045 wt %, or from about 0.02 to about0.045 wt %, or from about 0.03 to about 0.045 wt %.

In another aspect, the pharmaceutical composition comprises acombination of: (a) halobetasol or a pharmaceutically acceptable salt orester thereof; and (b) a tazarotene or a pharmaceutically acceptabletazarotenic acid salt or a pharmaceutically acceptable non-ethyl esterof tazarotenic acid, for treating psoriasis; wherein (a) halobetasol ora pharmaceutically acceptable salt or ester thereof is present in thecomposition at a concentration in the range from about 0.005 to about0.035 wt %, or from about 0.005 to about 0.025 wt %, or from about 0.01to about 0.025 wt %; and (b) tazarotene or a pharmaceutically acceptabletazarotenic acid salt or a pharmaceutically acceptable non-ethyl esterof tazarotenic acid is present in the composition at a concentration inthe range from about 0.001 to about 0.049 wt %, or from about 0.01 toabout 0.049 wt %, or from about 0.01 to about 0.045 wt %, or from about0.02 to about 0.04 wt %, or from about 0.02 to about 0.045 wt %, or fromabout 0.03 to about 0.045 wt %.

In still another aspect, the pharmaceutical composition comprises acombination of: (a) halobetasol or a pharmaceutically acceptable salt orester thereof at a concentration of 0.01 wt %; and (b) tazarotene at aconcentration of 0.045 wt %, or a pharmaceutically acceptabletazarotenic acid salt at a concentration that provides 0.045 wt % astazarotene, for treating psoriasis.

In still another aspect, the pharmaceutical composition comprises acombination of: (a) halobetasol or a pharmaceutically acceptable salt orester thereof at a concentration of 0.01 wt %; and (b) tazarotene at aconcentration of 0.045 wt %, or a pharmaceutically acceptable ester,other than ethyl ester, of tazarotenic acid at a concentration thatprovides 0.045 wt % as tazarotene, for treating psoriasis. Non-limitingexamples of non-ethyl esters of tazarotenic acid are disclosed hereinabove.

In yet another aspect, the pharmaceutical composition comprises acombination of: (a) halobetasol propionate at a concentration of 0.01 wt%; and (b) tazarotene at a concentration of 0.045 wt %, for treatingpsoriasis.

In one aspect, a topical pharmaceutical composition of the presentinvention is in the dosage form of gel, emulsion (including lotion,cream, and milk), shampoo, foam, suspension, liquid, spray, paste orointment. In certain preferred embodiments, a topical pharmaceuticalcomposition of the present invention is an oil-in-water emulsion, inwhich an internal oil phase is dispersed in a continuous aqueous phase.Alternatively, water-in-oil-in-water, water-in-oil andoil-in-water-in-oil emulsions are also contemplated. The emulsion may bea macroemulsion, a microemulsion, or a nanoemulsion. Also contemplatedare other formulations in which an oil phase and a water phase coexistwithin the formulation, such as a multivesicular emulsion, which is nota true emulsion, disclosed in Espinoza, U.S. Pat. No. 6,709,663. Alsocontemplated is a liposomal dispersion in a gel, cream or other dosageform. Also contemplated are other formulations in which non-polar andpolar liquid ingredients, with or without semipolar ingredients, coexistwith the formulation.

In addition to the active ingredients as disclosed above, a compositionof the present invention comprises one or more dermatologicallyacceptable excipients, such as liquid oils, waxes viscosity-modifyingagents, thickening agents, gelling agents, alcohols, surfactants,chelating agents, buffers, preservatives, humectants, emollients,stabilizers, diluents, dispersing agents, emulsifiers, wetting agents,stabilizers, pH adjusters, solvents or cosolvents.

The formulation of the invention may desirably contain a thickeningagent to provide viscosity so that the formulation may be provided inthe form of a lotion, gel, cream, or ointment. Preferably, but notnecessarily, the thickening agent is miscible or soluble in an aqueousfluid. Non-limiting examples of suitable thickening agents includeacacia, alginic acid and its salts, hyaluronic acid and its salts,carbomers (also known as carboxy vinyl polymers, which are cross-linkedpolyacrylic acid), carboxymethylcellulose, ethylcellulose, gelatin,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, poloxamers, polyvinylpyrrolidone, polyvinylalcohol, tragacanth, xanthan gum, magnesium aluminum silicate, andbentonite. The thickening agent may also reside in the oil or lipophilicportion of the formulation. Examples of suitable lipophilic thickeningagents include cetyl alcohol, stearyl alcohol, glyceryl stearate, whitebeeswax, microcrystalline wax, hydrogenated polyisobutene polymers, andemulsifying wax.

A suitable group of thickening agents is carbomers, such as Carbopol®and polycarbophil (The Lubrizol Corporation, Wickliffe, Ohio). Carbopol®homopolymers are polymers of acrylic acid crosslinked with allyl sucroseor allylpentaerythritol. Carbopol® copolymers are polymers of acrylicacid and C₁₀-C₃₀ alkyl acrylate crosslinked with allylpentaerythritol.Carbopol® interpolymers are carbomer homopolymers or copolymers thatcontain a block copolymer of polyethylene glycol and a long chain alkylacid ester. Noveon® polycarbophil is a polymer of acrylic acidcrosslinked with divinyl glycol.

A surfactant or emulsifier is included, if desired or required.Pharmaceutically acceptable anionic, cationic, or non-ionic surfactantsmay be included in a composition of the present invention. Non-ionicsurfactants are preferred. Non-limiting examples of non-ionicsurfactants are Octoxynol (also known as Macrogol tetramethylbutylphenylether, octylphenoxy polyethoxyethanol, or polyoxyethylene octylphenylether), such as Octoxynol 1, 3, 5, 8, 9, 10, 12, 13, 16, 30, 40, 70(wherein the number indicates the number of repeating oxyethyleneunits), or other Octoxynols that comprise different numbers of repeatingunits of oxyethylene in the side chain, sorbitan esters (such assorbitan monooleate and sorbitan monostearate, commonly known by theirtrade names Span 80 and Span 60), polysorbates (such as polysorbate 80(polyoxyethylene sorbitan monooleate), polysorbate 60 (polyoxyethylenesorbitan monostearate), polysorbate 20 (polyoxyethylene sorbitanmonolaurate), commonly known by their trade names of Tween® 80, Tween®60, Tween® 20), poloxamers (synthetic block polymers of ethylene oxideand propylene oxide, such as those commonly known by their trade namesof Pluronic®; e.g., Pluronic® F127 or Pluronic F108), or poloxamines(synthetic block polymers of ethylene oxide and propylene oxide attachedto ethylene diamine, such as those commonly known by their trade namesof Tetronic®; e.g., Tetronic® 1508 or Tetronic® 908, etc.), othernonionic surfactants such as Brij® (polyoxyethylene alkyl ether having aformula of CH₃—(CH₂)₁₀₋₁₆—(O—C₂H₄)₁₋₂₅—OH), Myrj® (stearic acidesterified with polyoxyethylene having 40-100 repeating oxyethyleneunits), and long chain fatty alcohols (e.g., oleyl alcohol, stearylalcohol, myristyl alcohol, docosahexaenoyl alcohol, etc.) with carbonchains having about 12 or more carbon atoms (e.g., such as from about 12to about 24 carbon atoms).

In addition, polymeric emulsifiers such as those known under the tradename Pemulen™ (The Lubrizol Corporation, Wickliffe, Ohio) may be used.These are polymers of acrylic acid, modified by long chain (C₁₀-C₃₀)alkyl acrylates, and crosslinked with allylpentaerythritol.

An anionic emulsifier may be used, such as sodium or potassium oleate,triethanolamine stearate, sodium lauryl sulfate, sodium dioctylsulfosuccinate, and sodium docusate. Less preferred are cationicemulsifiers such as quaternary ammonium salts. Still other emulsifiersinclude glyceryl monostearate, polyoxyethylene monooleate,polyoxyethylene monostearate, polyoxyethylene monolaurate, potassiumoleate, sodium lauryl sulfate, sodium oleate, sorbitan monolaurate,sorbitan monopalmitate, sorbitan monostearate, sorbitan tristearate,sorbitan monooleate, sorbitan trioleate, triethanolamine oleate,polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitanmonopalmitate, polyoxyethylene sorbitan monostearate, polyoxyethylenesorbitan tristearate, polyoxyethylene sorbitan monooleate, andpolyoxyethylene sorbitan trioleate.

The formulation desirably contains a dermatologically acceptablehumectant such as glycerin, sorbitol, hexylene glycol, propylene glycol,or urea. In addition, the formulation may contain an emollient such aspetrolatum, lanolin, mineral oil, light mineral oil, stearic acid,cyclomethicone, or dimethicone. Chelating agents such as EDTA and itssalts may be included in a formulation of the present invention.

The liquid oil component of the composition includes one or morematerials that are practically insoluble or insoluble in water and whichare liquid at room temperature. For example, in one embodiment, theliquid oil component of the composition includes one or more materialsthat are practically insoluble or insoluble in water and which areliquid at room temperature of 22° C. The liquid oil component may beselected from one or more ingredients from the group consisting ofdicarboxylic acid esters (“DCAE”), monocarboxylic acid esters (“MCAE”),fish-liver oil, long-chain triglycerides (wherein each side chain has14-18 carbons, such as peanut oil, sesame oil, coconut oil, sunfloweroil, corn oil, olive oil, cotton seed oil, or derivatives thereof),propylene glycol diesters, medium-chain triglycerides (such as thosewherein each side chains has 8-10 carbons; e.g., capric/caprylic acidtriglycerides), hydrocarbons like mineral oil, light mineral oil,squalene, and squalane, fatty alcohols (such as octyldodecanol andisostearyl alcohol), and fatty acids (such as isostearic acid and oleicacid).

In some embodiments, the liquid oil component comprises a dicarboxylicacid ester and light mineral oil. In some other embodiments, the liquidoil component comprises one or more long-chain triglycerides.

The formulation may include other lipophilic liquids in an amount thatis sufficient to be miscible with the dicarboxylic acid ester and/ormonocarboxylic acid ester. The lipophilic liquid may be an emollientsuch as lanolin oil, mineral oil, light mineral oil, isostearic acid,squalene, octyldodecanol, fractionated coconut oil, cyclomethicone, ordimethicone.

In addition to the liquid oil component, the formulation may containwater insoluble or practically insoluble ingredients that are not liquidat room temperature, but are soluble in the liquid oil component.

A DCAE that is suitable for the present invention has the formulaR₁OOC—(CH₂)_(n)—COOR₂, wherein R₁ and R₂ are alkyl groups containingbetween 1 and 4 carbons or aryl groups and may be the same or may bedifferent and wherein (CH₂)_(n) is a straight or branched chain and n isbetween 1 and 12. Examples of DCAEs containing one or more aryl groupsare dibenzyl esters of dicarboxylic acids A preferred dicarboxylic acidester is diethyl sebacate, which has the formulaCH₃CH₂OOC—(CH₂)₈—COOCH₂CH₃. Examples of other suitable dicarboxylic acidesters (where R₁ and R₂ are the same) are dimethyl, diethyl, dipropyl,diisopropyl, dibutyl and diisobutyl esters such as oxalate, malate,succinate, glutarate, adipate, pimelate, suberate, and azalate. Examplesof suitable dicarboxylic acid esters (where R₁ is different from R₂) aremethyl ethyl, methyl propyl, methyl butyl, methyl isopropyl, ethylpropyl, ethyl butyl, ethyl isopropyl, and propyl butyl esters such asoxalate, malate, succinate, glutarate, adipate, pimelate, suberate,azalate, and sebacate.

Alternatively, or in combination with the DCAE, the formulation maycontain a MCAE. The MCAE that is suitable for the present invention hasthe formula CH₃—(CH₂)_(n)—COOR₁, wherein R₁ is an alkyl group containingbetween 1 and 4 carbons or an aryl group, and wherein (CH₂)_(n) isstraight or branched chain and n is between 1 and 12. Examples of suchmonocarboxylic acid esters include methyl, ethyl, propyl, isopropyl,butyl, or an aryl such as benzyl formate, acetate, propionate, butyrate,valerate, laurate, myristate, palmitate, and stearate. Examples ofpreferred monocarboxylic acid esters are isopropyl palmitate andisopropyl myristate.

The liquid oil phase may beneficially be used to dissolve one or more ofthe active ingredients within the emulsion or other type of formulationof the present invention. In one embodiment the corticosteroid and theretinoid are both dissolved in the liquid oil phase within theformulation at room temperature. In another embodiment thecorticosteroid is dissolved in the liquid oil phase and the retinoid issuspended within the formulation at room temperature. In yet anotherembodiment the retinoid is dissolved in the liquid oil phase and thecorticosteroid is suspended within the formulation at room temperature.In the case wherein the retinoid or the corticosteroid is suspended inthe formulation, it is preferred that the suspended active ingredient bemicronized, namely that the mean particle size is preferably about 25microns in diameter or less.

In one aspect, a composition of the present invention comprises theingredients at the concentrations shown in Table 2.

TABLE 2 Compositions of the Present Invention for Treating PsoriasisConcentration (wt %) Ingredient Range 1 Range 2 Range 3 Class-1Corticosteroid 0.001-0.049  0.005-0.035  0.01-0.025 Tazarotene or0.01-0.049 0.02-0.045 0.03-0.045 Tazarotenic Acid Compound Emollient,Solvent, 0.5-40   1-25 2-20 and/or Thickener Emulsifier 0.25-10  0.5-7   1-5  Humectant 0-15 2-12 10 Polymeric Thickener 0.05-2   0.1-1.5  0.3-1   Pharmaceutical Aids q.s. q.s. q.s. Purified water q.s.to 100 q.s. to 100 q.s. to 100

Non-limiting examples of compositions of the present invention are shownin Table 3.

TABLE 3 Some Emulsion Compositions of the Present Invention for TreatingPsoriasis Concentration (wt %) Preferred Ingredient Function Range 1Range 2 Range 3 embodiment Halobetasol Class 1 0.001-0.04 0.005-0.03 0.005-0.02  0.01 propionate Corticosteroid Tazarotene Retinoid 0.02-0.049  0.03-0.049  0.04-0.049 0.045 Diethyl Liquid Oil &  1-5 2-42.5-3.5 2.97 sebacate Solvent Light mineral Liquid Oil & Co-  5-15  5-107.5-8.5 8.03 oil Solvent Sorbitan Surfactant/ 0.01-1   0.02-0.5 0.05-0.2  0.1 monooleate Emulsifying Agent Sorbitol Humectant  5-15 7-12 10-11 10.7 solution, 70% Methyl Antimicrobial 0.05-0.3 0.1-0.30.1-0.2 0.17 paraben Preservative⁽¹⁾ Propyl paraben Antimicrobial0.01-0.1 0.01-0.05 0.02-0.04 0.03 Preservative⁽¹⁾ Edetate Chelating0.02-0.1 0.02-0.7  0.03-0.06 0.05 disodium Agent⁽¹⁾ dihydrate CarbomerEmulsifying 0.1-1  0.2-0.7 0.3-0.5 0.4 copolymer type Agent B (e.g.,Pemulen ™ TR-1) Carbomer Thickener  0.2-1.5 0.3-1   0.5-0.7 0.6homopolymer type A (e.g., Carbomer 981) Sodium pH-adjusting q.s. to q.s.to pH q.s. to pH q.s. to pH of hydroxide, Agent⁽¹⁾ pH of of 5.5 ± 0.5 of5.5 ± 0.5 5.5 ± 0.5 10% Solution 5.5 ± 0.5 Purified water Carrier q.s.to 100 q.s. to 100 q.s. to 100 q.s. to 100 Note: ⁽¹⁾These ingredientsare broadly classified as Pharmaceutical Aids.

A lotion having a composition as shown in the last column of Table 2 wasprepared as follows.

A separate aqueous phase was made. In a manufacturing vessel equippedwith a mixing implement (such as a propeller) and temperature control,purified water and disodium edetate dihydrate were combined and themixture was agitated until a clear solution is achieved. Sorbitol,methylparaben, and propylparaben were then added to the mixture. Themixture was continuously mixed and was heated to approximately 75° C.The mixture was agitated until a solution was obtained. The mixture wasthen removed from the heat source and allowed to cool to below 40° C.with continued mixing. With continuous mixing, Carbopol® 981 was addedto the mixture and dispersed. Mixing continued until Carbopol® 981 wasfully dispersed and hydrated.

A separate oil phase was made. In a vessel equipped with a mixingimplement such as a propeller, diethyl sebacate, halobetasol propionate,and tazarotene were combined. The mixture was agitated until a solutionwas achieved. With continuous mixing, light mineral oil and sorbitanmonooleate were added. Mixing is continued until a solution is obtained.

In a separate vessel, a 1N solution of sodium hydroxide is prepared.

With high speed mixing, the oil phase containing the active ingredients(halobetasol propionate and tazarotene) was added to the aqueous phase.Pemulen™ TR-1 was slowly added into the mixture. Mixing was continueduntil a homogeneous emulsion was obtained. Mixing speed was decreasedand mixing continued for an additional time of 10 minutes to 1 hour.With continuous mixing, an appropriate amount of the sodium hydroxidesolution was added incrementally to obtain a pH of 5.5±0.5. Mixingcontinued further until a homogeneous lotion was obtained, such as for30 minutes to 3 hours.

Alternatively, Pemulen™ TR-1 may be added into the aqueous phase when itwas made.

A clinical study in psoriasis patients was conducted to compare theefficacy of a composition of the present invention containinghalobetasol propionate and tazarotene (“IDP-118”); placebo (“Vehicle”);a composition containing only halobetasol propionate (“HP”); and acomposition containing only tazarotene (“Taz”). The compositions for theclinical studies are shown in Table 4.

TABLE 4 Compositions for Clinical Studies Concentration (wt %) IDP-118Halobetasol (Present Placebo propionate Tazarotene Ingredient FunctionInvention) (Vehicle) only only Halobetasol Active 0.01 0 0.01 0propionate, Ingredient micronized Tazarotene Active 0.045 0 0 0.045Ingredient Diethyl Emollient & 2.97 2.97 2.97 2.97 sebacate SolventLight mineral oil Emollient & 8.03 8.03 8.03 8.03 Solvent SorbitanSurfactant/ 0.1 0.1 0.1 0.1 monooleate Emulsifying Agent SorbitolHumectant 10.7 10.7 10.7 10.7 solution, 70% Methyl paraben Antimicrobial0.17 0.17 0.17 0.17 Preservative Propyl paraben Antimicrobial 0.03 0.030.03 0.03 Preservative Edetate Chelating 0.05 0.05 0.05 0.05 disodiumAgent dihydrate Carbomer Emulsifying 0.4 0.4 0.4 0.4 copolymer typeAgent B (Pemulen ™ TR-1) Carbomer Thickener 0.6 0.6 0.6 0.6 homopolymertype A (Carbomer 981) Sodium pH-adjusting q.s. to pH q.s. to pH q.s. topH q.s. to pH hydroxide agent of 5.5 ± 0.5 of 5.5 ± 0.5 of 5.5 ± 0.5 of5.5 ± 0.5 Purified water Solvent q.s. to 100 q.s. to 100 q.s. to 100q.s. to 100

A double blind clinical study was conducted whereby neither thepsoriasis patient nor the investigator knew the identity of the testlotion assigned. The blindly labeled lotions were applied to thepsoriasis plaques once daily. All test lotions were the same except forthe differences is in active ingredients being studied. Approximately212 subjects were randomized in a 2:2:2:1 ratio to receive IDP-118 (acomposition of the present invention, comprising halobetasol propionate0.01% and tazarotene 0.045%) Lotion, HP (halobetasol propionate 0.01%)Lotion, Taz Lotion (tazarotene 0.045% and Lotion Vehicle (no activeingredients), as follows:

59 subjects to IDP-118 Lotion (“IDP 118 group”)

63 subjects to HP 0.01% Lotion (“HP group”)

59 subjects to Taz 0.045% Lotion (“Taz group”)

31 subjects to Lotion Vehicle (“Vehicle group”).

Eighteen investigative centers participated in the clinical study, eachfollowing the same protocol.

The key enrollment criteria were that each subject had at least moderateseverity of psoriasis; i.e., a score of 3 or 4, as defined by theInvestigator Global Assessment (“IGA”) scale shown in Table 5.

TABLE 5 Investigator's Global Assessment Score Grade Description 0 ClearNo evidence of scaling No evidence of erythema No evidence of plaqueelevation above normal skin level 1 Almost clear Some plaques with finescales Faint pink/light red erythema on most plaques Slight or barelyperceptible elevation of plaques above normal skin level 2 Mild Most toall plaques have some fine scales but are not fully covered, someplaques are completely covered with fine scale Most to all plaques arepink/light red to bright red in color Some plaques have definiteelevation above normal skin level, typically with edges that areindistinct and sloped on some of the plaques 3 Moderate Some plaques areat least partially covered with a coarse scale, most to all plaques arenearly covered with fine or course scale; Most to all plaques are brightred, some plaque may be dark red in color Definite elevation of most toall plaques; rounded or sloped edges on most of the plaques 4 SevereMost to all plaques are covered with coarse, thick scales Most or allplaques are bright, dark or dusky red Almost all plaques are raised andwell-demarcated; sharp edges on virtually all plaques

For each patient the investigator determined and recorded the treatableareas affected by psoriasis at the Baseline visit. Treatable areas weredefined as all areas of psoriasis identified at Baseline comprising abody surface area (BSA) of 3% to 12% and designated for treatment withstudy drug. According to protocol the treatable affected areas did notinclude the face, scalp, palms, soles, axillae, or intertriginous areas.If palms and soles were affected, study drug could be applied at thediscretion of the investigator; however, these areas were not includedin the treatable BSA or efficacy assessments. Also a target lesion(psoriasis plaque) was identified and at the Baseline visit to be usedsolely for assessment of three signs of psoriasis: erythema, plaqueelevation, and scaling.

The assigned study drug was applied topically to the affected area (asdetermined by the investigator at Baseline) once daily for 8 weeks. Theinitial application was made at the investigational center during theday as per instruction from the study coordinator or designee. Thesubjects were instructed to avoid exposure to direct sunlight to preventsunburn. Subjects applied their daily treatments at home as explained bythe study coordinator or designee at each investigational center. Thesubjects were asked to return their used containers of study drug attheir clinic visits on Weeks 2, 4, 6, and 8. Subjects were asked to notapply study drug on the day of a clinic visit until after assessmentswere completed at the clinic. The study coordinator or designee at eachinvestigational center dispensed 2 new containers of study drug to eachsubject at Baseline and Weeks 2, 4, and 6. Upon completion of the 8-weektreatment period all study drug supplies were turned-in to theinvestigational center, and all subjects were asked to return to theinvestigational center 4 weeks later for a post-treatment cessationfollow-up visit (Week 12). During the study, each subject was onlypermitted to use approved non-medicated cleansers and moisturizers; nosunscreens or other skin care products were permitted on the treatmentareas.

The investigator monitored the efficacy at each study visit by assessingthe treatable area and determining the IGA score for psoriasis severity,and grading the target lesion for erythema, plaque elevation, andscaling in each subject.

Information on reported and observed adverse events (“AEs”) was obtainedat each visit. An abbreviated physical examination was performed atBaseline, Week 8 (end of treatment), and Week 12 (the 4-weekpost-treatment cessation follow-up visit) for all subjects.

The signs of psoriasis (erythema, plaque elevation, and scaling) wereassessed for the selected target lesion using the grading scalesdisplayed in Table 4. Improvements in these signs are a measure of theefficacy of a studied drug. Efficacy assessment was made at 2, 4, 6, and8 weeks during the treatment phase and at the 12-week visit (the 4-weekpost treatment follow-up visit).

Tolerability was evaluated through assessments of selected local signsand symptoms (itching, dryness, and burning/stinging). In addition, thetreatment areas were examined by the evaluator at each visit forpresence or absence of significant known drug-related adverse events:skin atrophy, striae, telangiectasia, and folliculitis.

Efficacy of the four study drugs was assessed based on the IGA scores,that is improvement in the IGA psoriasis severity score over time.

Clinical Efficacy was determined based on the percentage of subjects whowere treatment successes.

The IDP-118 group was compared to each of the other treatment groups:(1) HP group, (2) Taz group, and (3) Vehicle group.

To be judged as a treatment success, subjects had to show two-gradeimprovement in IGA from the baseline, and to have an IGA score of“clear, or almost clear” at the evaluation time. Subjects not achievingtreatment success by this standard were considered treatment failures,even though such subjects may have experienced some degree ofimprovement in their psoriasis.

Results

The efficacy of IDP-118 comprising Halobetasol Propionate 0.01% andTazarotene 0.045% is shown and discussed.

After completion of the clinical study the blinding codes were brokenand the results tabulated. Data for dichotomized IGA with subjectscategorized as Treatment Success or Failures are presented in Table 6.

As required by FDA success was defined as at least a two-gradeimprovement from Baseline in the IGA score and an IGA score equating to‘Clear’ or ‘Almost Clear’. Also shown in Table 7 is the statisticalanalysis of IDP-118 compared to each of the other treatment groups basedon the percentage of subjects achieving Treatment Success. P-values arefrom a Cochran-Mantel-Haenszel test using pairwise tests comparingIDP-118 to Vehicle, IDP-118 to HP and IDP-118 to Taz. Week 12 is thefollow-up evaluation time, 4 weeks after the end of treatment.

TABLE 6 Treatment Successes and Failures Based on Improvement in IGAScore IDP-118 HP 0.01% Taz 0.045% Vehicle Dichotomized IGA^((a)) (N =59) (N = 63) (N = 59) (N = 31) Week 2 No. of Subjects 59 63 59 31Success 7 3 1 0 Failure 52 60 58 31 p-value^((b)) 0.155 0.029 0.047 Week4 No. of Subjects 59 63 59 31 Success 15 11 1 2 Failure 44 52 58 29p-value^((b)) 0.285 <0.001 0.030 Week 6 No. of Subjects 59 63 59 31Success 19 16 9 1 Failure 40 47 50 30 p-value^((b)) 0.408 0.031 0.002Week 8 No. of Subjects 59 63 59 31 Success 31 21 11 3 Failure 28 42 4828 p-value^((b)) 0.033 <0.001 <0.001 Week 12 No. of Subjects 55 62 47 29Success 21 13 6 2 Failure 34 49 41 27 p-value^((b)) 0.042 0.004 0.002^((a))Success was defined as at least a two-grade improvement fromBaseline in the IGA score and an IGA score equating to ‘Clear’ or‘Almost Clear’. ^((b))p-value from a Cochran-Mantel-Haenszel test.Pairwise tests were conducted comparing IDP-118 to Vehicle and IDP-118to HP or Taz.

TABLE 7 Percentage of Subjects Achieving Treatment Success HP TazDuration IDP-118 0.01% 0.045% Vehicle Week 2 11.9 4.8 1.7 0 Week 4 25.417.5 1.7 6.5 Week 8 52.5 33.3 18.6 9.7 Week 12 38.2 21.0 12.8 6.9

Actual Clinical Efficacy compared to Predicted Additive ClinicalEfficacy (as a percentage of subjects achieving “Treatment Success”) isshown in Table 8. The “Treatment Success” percentages for the activetreatment groups (IDP-118, HP, and Taz) were corrected for vehicleeffect by subtracting the actual Vehicle group results from each todetermine the net Treatment Success are shown as a percentage of thenumber of subjects treated.

TABLE 8 Comparative Treatment Success Rates for IDP-118, HP, and TazGroups Control-Adjusted Percentage of Patients Achieving TreatmentSuccess During the Study HP Taz HP + Taz IDP-118 Duration Actual ActualCalculated Actual Week 2 4.8 1.7 6.5 11.9 Week 4 11 −4.8 6.2 18.9 Week 823.6 8.9 32.5 42.8

The synergistic effect of IDP-118 is illustrated by comparing theclinical efficacy from IDP-118 to the predicted efficacy from combiningHP and Taz (see Table 9). The control-adjusted percentage of patientswho were successfully treated with IDP-118 was greater than the sum ofcontrol-adjusted percentages of patients who were successfully treatedsingly with HP and Taz at all evaluation times: 2 weeks of treatment, 4weeks of treatment, 8 weeks of treatment, and 4 weeks after thecompletion of 8 weeks of treatment (Week 12).

TABLE 9 Synergistic Clinical Efficacy of IDP-118 at weeks 2, 4, 8 and 12Percent of Patients Achieving Treatment Success Ratio of IDP-118 Actualto Duration Actual HP + Taz Calculated Expected Week 2 11.9 6.5 1.8 Week4 18.9 6.2 3.0 Week 8 42.8 32.5 1.3 Week 12 31.3 20 1.6

The efficacy of IDP-118 was compared to that of HP (halobetasolpropionate 0.01%), Taz (tazarotene 0.045%) and the placebo (vehicle ofIDP-118) in terms of success in resolving erythema, plaque elevation,and scaling. The results are shown in Tables 10-12. The success rate forIDP-118 is higher than that of HP, and much higher than those for Tazand placebo. These comparisons were made on assessments of a targetlesion that was identified at baseline before treatment was commenced.

The percentage of patients who experienced adverse events, as indicatedby itching, burning, and stinging, is much lower for those who weretreated with IDP-118 than those treated with HP or Taz. The results areshown in Table 13.

TABLE 10 Severity of Erythema Through Time Baseline Week 2 Week 4 Week 6Week 8 Week 12 IDP-118 Erythema Number of Subjects 59 59 59 59 59 550—None 0.0% 0.0% 10.2% 6.8% 11.9% 16.4% 1—Minimum 0.0% 23.7% 32.2% 37.3%44.1% 32.7% 2—Mild 6.8% 37.3% 30.5% 35.6% 28.8% 32.7% 3—Moderate 89.8%39.0% 25.4% 18.6% 15.3% 18.2% 4—Severe 3.4% 0.0% 1.7% 1.7% 0.0% 0.0% HP0.01% Erythema Number of Subjects 63 63 63 63 63 62 0—None 0.0% 3.2%7.9% 12.7% 14.3% 11.3% 1—Minimum 0.0% 12.7% 33.3% 34.9% 33.3% 29.0%2—Mild 7.9% 38.1% 23.8% 27.0% 33.3% 22.6% 3—Moderate 84.1% 44.4% 34.9%25.4% 17.5% 33.9% 4—Severe 7.9% 1.6% 0.0% 0.0% 1.6% 3.2% Taz 0.045%Erythema Number of Subjects 59 59 59 59 59 47 0—None 0.0% 0.0% 3.4% 1.7%1.7% 4.3% 1—Minimum 0.0% 5.1% 5.1% 20.3% 20.3% 25.5% 2—Mild 8.5% 22.0%42.4% 30.5% 32.2% 36.2% 3—Moderate 81.4% 57.6% 37.3% 39.0% 37.3% 34.0%4—Severe 10.2% 15.3% 11.9% 8.5% 8.5% 0.0% Vehicle (N = 31) ErythemaNumber of Subjects 31 31 31 31 31 29 0—Clear 0.0% 0.0% 3.2% 0.0% 3.2%0.0% 1—None 0.0% 9.7% 6.5% 16.1% 9.7% 10.3% 2—Minimum 6.5% 25.8% 19.4%12.9% 25.8% 34.5% 3—Moderate 87.1% 58.1% 61.3% 67.7% 54.8% 51.7%4—Severe 6.5% 6.5% 9.7% 3.2% 6.5% 3.4%

TABLE 11 Degree of Plaque Elevation Through Time Baseline Week 2 Week 4Week 6 Week 8 Week 12 IDP-118 Plaque Elevation Number of Subjects 59 5959 59 59 55 0—None 0.0% 10.2% 28.8% 33.9% 40.7% 32.7% 1—Minimum 0.0%37.3% 32.2% 28.8% 32.2% 21.8% 2—Mild 15.3% 35.6% 23.7% 23.7% 16.9% 30.9%3—Moderate 79.7% 15.3% 13.6% 13.6% 10.2% 12.7% 4—Severe 5.1% 1.7% 1.7%0.0% 0.0% 1.8% HP 0.01% Plaque Elevation Number of Subjects 63 63 63 6363 62 0—None 0.0% 9.5% 17.5% 20.6% 25.4% 22.6% 1—Minimum 0.0% 14.3%17.5% 33.3% 33.3% 30.6% 2—Mild 17.5% 27.0% 36.5% 27.0% 22.2% 21.0%3—Moderate 73.0% 44.4% 27.0% 17.5% 17.5% 22.6% 4—Severe 9.5% 4.8% 1.6%1.6% 1.6% 3.2% 0.045% Plaque Elevation Number of Subjects 59 59 59 59 5947 0—None 0.0% 3.4% 3.4% 5.1% 5.1% 10.6% 1—Minimum 0.0% 10.2% 28.8%44.1% 39.0% 23.4% 2—Mild 10.2% 40.7% 35.6% 23.7% 30.5% 31.9% 3—Moderate84.7% 42.4% 27.1% 23.7% 20.3% 31.9% 4—Severe 5.1% 3.4% 5.1% 3.4% 5.1%2.1% Vehicle Plaque Elevation Number of Subjects 31 31 31 31 31 290—Clear 0.0% 0.0% 3.2% 3.2% 6.5% 0.0% 1—None 0.0% 6.5% 9.7% 3.2% 12.9%17.2% 2—Minimum 12.9% 29.0% 22.6% 29.0% 19.4% 37.9% 3—Moderate 71.0%61.3% 61.3% 61.3% 51.6% 34.5% 4—Severe 16.1% 3.2% 3.2% 3.2% 9.7% 10.3%

TABLE 12 Degree of Scaling Through Time Baseline Week 2 Week 4 Week 6Week 8 Week 12 IDP-118 Scaling Number of Subjects 59 59 59 59 59 550—None 0.0% 6.8% 20.3% 20.3% 37.3% 29.1% 1—Minimum 0.0% 37.3% 39.0%50.8% 35.6% 38.2% 2—Mild 16.9% 33.9% 33.9% 25.4% 18.6% 21.8% 3—Moderate76.3% 20.3% 6.8% 3.4% 8.5% 10.9% 4—Severe 6.8% 1.7% 0.0% 0.0% 0.0% 0.0%HP 0.01% Scaling Number of Subjects 63 63 63 63 63 62 0—None 0.0% 4.8%17.5% 20.6% 30.2% 21.0% 1—Minimum 0.0% 22.2% 27.0% 33.3% 33.3% 30.6%2—Mild 15.9% 36.5% 36.5% 28.6% 22.2% 24.2% 3—Moderate 73.0% 33.3% 17.5%15.9% 12.7% 21.0% 4—Severe 11.1% 3.2% 1.6%) 1.6% 1.6%) 3.2% Taz 0.045%Scaling Number of Subjects 59 59 59 59 59 47 0—None 0.0% 1.7% 0.0% 3.4%1.7% 8.5% 1—Minimum 0.0% 13.6% 23.7% 37.3% 37.3% 27.7% 2—Mild 27.1%37.3% 40.7% 22.0% 22.0% 25.5% 3—Moderate 62.7% 39.0% 30.5% 33.9% 35.6%36.2% 4—Severe 10.2%) 8.5% 5.1% 3.4% 3.4% 2.1% Vehicle Scaling Number ofSubjects 31 31 31 31 31 29 0—Clear 0.0% 0.0% 3.2% 0.0% 12.9% 3.4% 1—None0.0% 6.5% 19.4% 19.4% 16.1% 17.2% 2—Minimum 16.1% 38.7% 25.8% 22.6%25.8% 37.9% 3—Moderate 67.7% 48.4% 41.9% 48.4% 38.7% 37.9% 4—Severe16.1%) 6.5% 9.7% 9.7% 6.5% 3.4%

TABLE 13 Frequency of Local Skin Reactions Through Time Baseline Week 2Week 4 Week 6 Week 8 Week 12 Itching IDP-118 Number of Subjects 59 59 5757 55 55 0—None 35.6% 52.5% 50.9% 57.9% 63.6% 67.3% 1—Mild 23.7% 33.9%40.4% 35.1% 20.0% 25.5% 2—Moderate 39.0% 11.9%) 8.8% 5.3% 12.7% 7.3%3—Severe 1.7% 1.7% 0.0% 1.8%) 3.6% 0.0% HP 0.01% Number of Subjects 6262 62 61 62 62 0—None 32.3% 46.8% 58.1% 59.0% 72.6% 38.7% 1—Mild 21.0%30.6% 32.3% 31.1% 16.1% 30.6% 2—Moderate 32.3% 19.4% 9.7% 9.8% 11.3%21.0% 3—Severe 14.5% 3.2% 0.0% 0.0% 0.0% 9.7% Taz 0.045% Number ofSubjects 58 57 48 49 47 47 0—None 29.3% 35.1% 35.4% 32.7% 36.2% 46.8%1—Mild 22.4% 26.3% 31.3% 36.7% 34.0% 38.3% 2—Moderate 41.4% 26.3% 27.1%24.5% 23.4% 12.8% 3—Severe 6.9% 12.3% 6.3% 6.1% 6.4% 2.1% Vehicle Numberof Subjects 31 31 31 31 30 29 0—None 22.6% 35.5% 45.2% 38.7% 33.3% 48.3%1—Mild 29.0% 35.5% 25.8% 25.8% 33.3% 27.6% 2—Moderate 38.7% 19.4% 16.1%25.8% 23.3% 20.7% 3—Severe 9.7% 9.7% 12.9% 9.7% 10.0% 3.4%Burning/Stinging IDP-118 Number of Subjects 59 59 57 57 55 55 0—None71.2% 79.7% 73.7% 77.2% 70.9% 89.1% 1—Mild 10.2% 13.6% 15.8% 12.3% 21.8%10.9% 2—Moderate 18.6% 6.8% 10.5% 8.8% 7.3% 0.0% 3—Severe 0.0% 0.0% 0.0%1.8% 0.0% 0.0% HP 0.01% Number of Subjects 62 62 62 61 62 62 0—None62.9% 77.4% 79.0% 88.5% 91.9% 83.9% 1—Mild 11.3% 14.5% 16.1% 9.8% 6.5%9.7% 2—Moderate 19.4% 6.5% 4.8% 1.6% 1.6% 4.8% 3—Severe 6.5% 1.6% 0.0%0.0% 0.0% 1.6% Taz 0.045% Number of Subjects 58 57 48 49 47 47 0—None72.4% 63.2% 64.6% 57.1% 68.1% 85.1% 1—Mild 10.3% 17.5% 18.8% 30.6% 19.1%10.6% 2—Moderate 17.2% 12.3% 14.6% 8.2% 12.8% 4.3% 3—Severe 0.0% 7.0%2.1% 4.1% 0.0% 0.0% Vehicle Number of Subjects 31 31 31 31 30 29 0—None54.8% 71.0% 74.2% 71.0% 76.7% 72.4% 1—Mild 19.4% 19.4% 16.1% 22.6% 3.3%6.9% 2—Moderate 22.6% 6.5% 3.2% 3.2% 13.3% 17.2% 3—Severe 3.2% 3.2% 6.5%3.2% 6.7% 3.4%

IDP-118 was consistently more effective than HP 0.01%, Taz 0.045%, orvehicle in achieving treatment success, defined as at least a two-gradeimprovement from Baseline in the IGA score at baseline and a score ofClear or Almost Clear at the evaluation time. IDP-118 demonstratedstatistically significant superiority over vehicle as early as two weeksafter starting treatment. At Week 8 end of treatment, 52.5% of subjectsin the IDP-118 group had treatment success compared with 33.3% in the HPgroup, 18.6% in the Taz group, and 9.7% in the Vehicle group (see Table5). Pairwise tests comparing IDP-118 with vehicle and HP 0.01% or Taz0.045% showed statistically significant treatment group differences atboth Week 8 (end of treatment) and Week 12 (4-week post-treatmentfollow-up). Of the subjects in the IDP-118 group who achieved treatmentsuccess at Week 8, more than half maintained status (treatment success)at Week 12 some four weeks after the completion of daily application ofthe test material, demonstrating the absence of a corticosteroid reboundeffect.

Mean absolute and percent changes in the IGA score from Baseline at eachvisit were consistent with the results of the dichotomized IGA. At Week8, the mean change from Baseline IGA score was −1.42 in the IDP-118group compared with −1.24 in the HP group, −0.64 in the Taz group, and−0.42 in the Vehicle group.

There were no serious adverse reactions reported in any of the patientstreated with IDP-118 during the eight-week period of daily applicationof the composition or the four-week medication-free follow-up period.

In another aspect, the present invention provides a method for treatingpsoriasis. The method comprises topically applying to an affected areaof the body of a subject suffering from psoriasis any one of thecompositions of the present invention, as disclosed herein, one or moretimes per day for a period of time sufficient to treat such psoriasis.For example, such a period of time may be 1 to 30 days or longer asneeded For example, such a period of time may be one week, two weeks,four weeks, eight weeks, twelve weeks, or longer as needed. For example,a composition of the present invention is applied topically to affectedareas of the body once per day for 7-14 days. Alternatively, it may beapplied two or three times per day for 7-14 days. Alternatively, it maybe applied once per day for one week to six months. For example, it maybe applied once per day for two weeks, four weeks, eight weeks, ortwelve weeks. In one embodiment, the treatment may be stopped for 1-7days (e.g., 2, 3, 4, 5, 6, or 7 days) after an extended treatment periodbefore it is resumed for another extended treatment period. Such anextended period may be 7 days, 7-14 days, 7-21 days, 7-30 days, orlonger before more treatment is needed or desired.

In yet another aspect, the present invention provides a method oftreating psoriasis topically with pharmaceutical composition comprisinga combination of: (a) halobetasol or a pharmaceutically acceptable saltor ester thereof; and (b) a tazarotene or a pharmaceutically acceptabletazarotenic acid salt, or ester; wherein each of: (a) halobetasol or apharmaceutically acceptable salt, or ester thereof; and (b) tazaroteneor a pharmaceutically acceptable tazarotenic acid salt, or ester ispresent in the composition at a positive concentration of less than0.05% based on the weight of the composition; wherein the clinicalefficacy of the combination is greater than that of either thehalobetasol component or the tazarotene component at the sameconcentration when used alone.

In yet another aspect, the present invention provides a method oftreating psoriasis topically with pharmaceutical composition comprisinga combination of: (a) halobetasol or a pharmaceutically acceptable salt,or ester thereof; and (b) a tazarotene or a pharmaceutically acceptabletazarotenic acid salt, or ester; wherein each of: (a) halobetasol or apharmaceutically acceptable salt, or ester thereof; and (b) tazaroteneor a pharmaceutically acceptable tazarotenic acid salt, or ester ispresent in the composition at a positive concentration of less than0.05% based on the weight of the composition; wherein the clinicalsuccess rate of the combination is synergistic compared to the clinicalsuccess rate of the halobetasol component at the same concentration usedalone plus the clinical success rate of the tazarotene component usedalone at the same concentration.

In yet another aspect, the present invention provides topicalpharmaceutical compositions comprising a combination of: (a) halobetasolor a pharmaceutically acceptable salt, or ester thereof; and (b) atazarotene or a pharmaceutically acceptable tazarotenic acid salt, orester thereof, and methods using the same, for treating psoriasis;wherein the pharmaceutical composition is a cream, lotion, ointment,gel, shampoo, suspension, paste, plaster, foam, spray or solution.Prophetic examples of formulations of some of these types areillustrated in Table 14.

In yet another aspect, the present invention provides a method oftreating psoriasis topically with pharmaceutical composition comprisinga combination of: (a) halobetasol or a pharmaceutically acceptable salt,or ester thereof; and (b) a tazarotene or a pharmaceutically acceptabletazarotenic acid salt, or ester; wherein the composition is applied atleast once daily for 4 weeks, such as for 6 weeks or 8 weeks.

In yet another aspect, the present invention provides a method oftreating psoriasis topically with pharmaceutical composition comprisinga combination of: (a) halobetasol or a pharmaceutically acceptable salt,or ester thereof; and (b) a tazarotene or a pharmaceutically acceptabletazarotenic acid salt, or ester; wherein the composition is applied oncedaily for more than 2 weeks, such as 4 weeks, for 6 weeks or for 8 weekswithout any serious adverse events (side effects).

In yet another aspect, a composition of the present invention that canbe used in any of the methods disclosed herein can be in the form of asolution, a spray, a milk, a foam, or an ointment. Non-limiting examplesof these compositions are shown in Table 14.

TABLE 14 Examples of Various Dosage Forms of Compositions of the PresentInvention Solution Spray Milk Foam Ointment Ingredient Concentration (%wt) Corticosteroid  0.001-0.049  0.001-0.049 0.001-0.049 0.001-0.0490.001-0.049 Tazarotene or tazarotenic acid  0.01-0.049  0.01-0.049 0.01-0.049  0.01-0.049  0.01-0.049 Humectant    0-15.0    0-15.0  0-15.0   0-15.0 — Antimicrobial preservative 0.01-0.4 0.01-0.40.01-0.4  0.01-0.4  — Chelating agent 0.02-0.1 0.02-0.1 0.02-0.1 0.02-0.1  — Emollients/Lipophilic Solvents qsad 100  0.5-50.0  0.5-50.0 0.5-50.0  0.5-50.0 Volatile solvent — qsad 100 — — — Non-ionicpolyethoxylated compounds — — — — — Non-ionic sorbitan compounds — —0.5-5.0 — 0.5-5.0 Polyoxyethylene fatty ethers — — — 0.5-10.0 — Fattyalcohols — — —   1-8.0  1.0-10.0 Petrolatum — — — — qsad 100Pharmaceutical aids (pH adjustment) — — 0.1-5.0 0.1-5.0 — Purified water— — qsad 100 qsad 100 —

In still another aspect, a composition of the present invention may beused in conjunction with another method of treatment of psoriasis, suchas phototherapy (e.g., with ultraviolet light).

In yet another aspect, a composition of the present invention may beused in conjunction with another medicament for treating psoriasis. Suchother medicament may be an anti-TNF-α agent (e.g., infliximab,etanercept, adalimumab, or golimumab), an agent targeting the Th17/IL-23axis (e.g., ustekinumab or briakinumab), a protein kinase C inhibitor(e.g., AEB071), a mitogen-activated protein kinase inhibitor (e.g.,BMS-582949), a FMS-like tyrosine kinase inhibitor (e.g., lestaurtinib),a Janus kinase inhibitor tofacitinib, ASP-015K, or INCB018424), aphosphodiesterase 4 inhibitor (e.g., apremilast, AN2728, or MK0873), anerve growth factor inhibitor (e.g., CF101), an anti-folate agent (e.g.,methotrexate, aminopterin, or BCX-4208), a calcineurin inhibitor (e.g.,cyclosporine), an anti-angiogenic agent (e.g., anti-VEGF antibody orsoluble VEGFR), or a vitamin D analog or derivative. Such othermedicament may be administered to a patient at substantially the sametime or at a different time. Such other medication may be administeredtopically, orally, or by injection or infusion.

While the present disclosure shows and describes a number of exemplaryembodiments, it will be manifest to those skilled in the art thatvarious further modifications may be made without departing from thespirit and scope of the underlying inventive concept and that the sameis not limited to particular compositions, processes, methods, orstructures herein shown and described.

What is claimed is:
 1. A topical pharmaceutical composition for treatingpsoriasis the composition comprising: (a) a corticosteroid or apharmaceutically acceptable salt or ester thereof, at a positiveconcentration of less than 0.05 percent by weight of the composition;(b) a retinoid or a pharmaceutically acceptable salt or ester thereof ata positive concentration of less than 0.09 percent by weight of thecomposition; and (c) a dermatologically acceptable carrier; wherein thecorticosteroid is selected from the group consisting of halobetasol,clobetasol, betamethasone, diflorasone, and fluocinonide.
 2. The topicalpharmaceutical composition of claim 1, wherein the corticosteroid or apharmaceutically acceptable salt or ester thereof is selected from thegroup consisting of halobetasol propionate, clobetasol propionate,betamethasone dipropionate, diflorasone diacetate, and fluocinonide. 3.The topical pharmaceutical composition of claim 1, wherein the retinoidis selected from the group consisting of tazarotene, bexarotene, andadapalene.
 4. The topical pharmaceutical composition of claim 1, whereinthe corticosteroid is halobetasol propionate, and the retinoid istazarotene.
 5. The topical pharmaceutical composition of claim 1,wherein (a) the corticosteroid is halobetasol or a pharmaceuticallyacceptable salt or ester thereof, and (b) the retinoid is tazarotene ora pharmaceutically acceptable tazarotenic acid salt, wherein (a)halobetasol or a pharmaceutically acceptable salt or ester thereof ispresent in the composition at a concentration in the range from about0.005 to about 0.03 percent by weight of the composition, and (b)tazarotene or a pharmaceutically acceptable tazarotenic acid salt ispresent in the composition at a concentration in the range from about0.005 to about 0.049 percent by weight of the composition.
 6. Thetopical pharmaceutical composition of claim 1, comprising: (a)halobetasol propionate at a concentration of 0.01 percent by weight ofthe composition; and (b) tazarotene at a concentration of 0.045 percentby weight of the composition.
 7. The topical pharmaceutical compositionof claim 1, wherein the composition is an oil-in-water emulsion.
 8. Thetopical pharmaceutical composition of claim 7, wherein thecorticosteroid and the retinoid are dissolved in a liquid oil componentof the emulsion.
 9. The topical pharmaceutical composition of claim 7,wherein the liquid oil component comprises a DCAE, MCAE, or combinationsthereof.
 10. The topical pharmaceutical composition of claim 8, whereinthe liquid oil component is selected from the group consisting of DCAE,MCAE, combinations thereof, and mixtures thereof.
 11. The topicalpharmaceutical composition of claim 7, wherein an oil phase of theoil-in-water emulsion comprises a liquid oil component, which comprisesdiethyl sebacate and light mineral oil.
 12. The topical pharmaceuticalcomposition of claim 11, wherein the corticosteroid and the retinoid aredissolved in the liquid oil component of the emulsion.
 13. The topicalpharmaceutical composition of claim 7, wherein the emulsion is a lotion.14. The topical pharmaceutical composition of claim 7, wherein theemulsion is a cream.
 15. A method of treating psoriasis, the methodcomprising topically applying a pharmaceutical composition to anaffected area of a body of a subject suffering from psoriasis; whereinthe composition comprises: (a) a corticosteroid or a pharmaceuticallyacceptable salt or ester thereof, at a positive concentration of lessthan 0.05 percent by weight of the composition; (b) a retinoid or apharmaceutically acceptable salt or ester thereof at a positiveconcentration of less than 0.09 percent by weight of the composition;and (c) a dermatologically acceptable carrier; wherein thecorticosteroid is selected from the group consisting of halobetasol,clobetasol, betamethasone, diflorasone, and fluocinonide; and whereinsaid applying is carried out one or more times per day for a period oftime sufficient to treat such psoriasis.
 16. The method of claim 15,wherein said applying is carried out once per day for eight weeks. 17.The method of claim 15, wherein the corticosteroid or a pharmaceuticallyacceptable salt or ester thereof is selected from the group consistingof halobetasol propionate, clobetasol propionate, betamethasonedipropionate, diflorasone diacetate, and fluocinonide.
 18. The method ofclaim 15, wherein the retinoid is selected from the group consisting oftazarotene, bexarotene, and adapalene.
 19. The method of claim 15,wherein the corticosteroid is halobetasol propionate, and the retinoidis tazarotene.
 20. The method of claim 15, wherein (a) thecorticosteroid is halobetasol or a pharmaceutically acceptable salt orester thereof; and (b) the retinoid is tazarotene or a pharmaceuticallyacceptable tazarotenic acid salt; wherein (a) halobetasol or apharmaceutically acceptable salt or ester thereof is present in thecomposition at a concentration in the range from about 0.005 to about0.03 percent by weight of the composition; and (b) tazarotene or apharmaceutically acceptable tazarotenic acid salt is present in thecomposition at a concentration in the range from about 0.005 to about0.049 percent by weight of the composition.
 21. The method of claim 15comprising: (a) halobetasol propionate at a concentration of 0.01percent by weight of the composition, and (b) tazarotene at aconcentration of 0.045 percent by weight of the composition.
 22. Themethod of claim 15, wherein the composition is an oil-in-water emulsion.23. The method of claim 22, wherein the corticosteroid and the retinoidare dissolved in a liquid oil component of the emulsion.
 24. The methodof claim 22, wherein the liquid oil component comprises a DCAE, MCAE, orcombinations thereof.
 25. The method of claim 23, wherein the liquid oilcomponent comprises a DCAE, MCAE, or combinations thereof.
 26. Themethod of claim 22, wherein an oil phase of the oil-in-water emulsioncomprises a liquid oil component, which comprises diethyl sebacate andlight mineral oil.
 27. The method of claim 26, wherein thecorticosteroid and the retinoid are dissolved in the liquid oilcomponent of the emulsion.
 28. The method of claim 22, wherein theemulsion is a lotion.
 29. The method of claim 22, wherein the emulsionis a cream.
 30. The method of claim 21, wherein said applying is carriedout once per day for eight weeks.